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antihypertensive drug (trade names Trandate and Normodyne) that blocks alpha and beta-adrenergic receptors of the sympathetic nervous system (leading to a decrease in blood pressure) (同)labetalol_hydrochloride, Trandate, Normodyne

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/10/04 16:54:55」(JST)

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Labetalol (Normodyne, Trandate) is a mixed alpha/beta adrenergic antagonist, which is used to treat high blood pressure.^[1]

Indications

It has a particular indication in the treatment of pregnancy-induced hypertension which is commonly associated with pre-eclampsia.^[2]

It is also used to treat chronic and acute hypertension of pheochromocytoma and hypertensive crisis.^[3](sany)

Administration

Labetalol is available in 100, 200, and 300 mg tablets and intravenously (available as Trandate) in 5 mg/ml solution. Adults taking tablets usually start with 100 mg twice daily, with a maximum of 2.4 g/day. In cases of emergency, dosage might be higher. Intravenous (IV) doses are usually started at 20 mg over two minutes. Additional doses of 40 mg, then 80 mg may be administered every ten minutes as needed. Additional 80 mg doses can be given to a total maximum dose of 300 mg. Additionally, labetalol can be administered by IV infusion at a rate of 2 mg/minute, with a maximum dose of 300 mg.

Side effects

Side effects may include:

Drowsiness
Fatigue
Weakness
Difficulty sleeping
Diminished sexual function
Orthostatic hypotension (due to alpha receptor blockade)
Scalp tingling
Hyperkalemia
Hepatotoxicity
Drug eruption similar to lichen planus^[4]
A rare but potentially lethal side effect is respiratory distress.

Contraindications

Labetalol has relative contraindications for use in patients with asthma, congestive heart failure, any degree of heart block, bradycardia, hypotension or those in cardiogenic shock.

Chemistry

For adrenergic agents, when the substituent on the amine nitrogen is greater in size than a t-butyl group, then the molecule typically is found to have receptor affinity without intrinsic activity, and is therefore an antagonist.^[5] Labetalol has two chiral carbons and consequently exists as four stereoisomers.^[6] Two of these isomers, the (S,S)- and (R,S)- forms are inactive. The third, the (S,R)-isomer, is a powerful α₁ blocker. The fourth isomer, the (R,R)-isomer which is also known as dilevalol, is a mixed nonselective β blocker and selective α₁ blocker.

Labetalol acts by blocking alpha and beta adrenergic receptors, resulting in decreased peripheral vascular resistance without significant alteration of heart rate or cardiac output. The β:α antagonism of labetalol is approximately 3:1.^[3]^[7]

Synthesis

Labetalol, 2-hydroxy-5-[1-hydroxy-2-[(1-methyl-3-phenylpropanol)amino)]ethyl] benzamide is synthesized by the N-alkylation of N-benzyl-N(4-phenyl-2-butyl)amine 5-bromacetylsalicylamide and forming the aminoketone, which is further debenzylated by hydrogen using a palladium–platinum on carbon catalyst into labetalol. Presumably the ketone is also reduced in this last step.

H.C. Welch, DE 2032642 (1971)
L.H.C. Lunts, D.T. Collin, U.S. Patent 4,012,444 (1977)
Clifton, J. E.; Collins, I.; Hallett, P.; Hartley, D.; Lunts, L. H. C.; Wicks, P. D. (1982). "Arylethanolamines derived from salicylamide with .alpha.- and .beta.-adrenoceptor blocking activities. Preparation of labetalol, its enantiomers and related salicylamides". Journal of Medicinal Chemistry 25 (6): 670. doi:10.1021/jm00348a013. PMID 6124636. edit

Mechanism of action

Labetalol combines both selective, competitive, alpha-1-adrenergic blocking and nonselective, competitive, beta-adrenergic blocking activity in a single substance. In man, the ratios of alpha- to beta- blockade have been estimated to be approximately 1:3 and 1:7 following oral and intravenous (IV) administration, respectively. The principal physiologic action of labetalol is to competitively block adrenergic stimulation of β-receptors within the myocardium (β1-receptors) and within bronchial and vascular smooth muscle (β2-receptors), and α1-receptors within vascular smooth muscle. This causes a decrease in systemic arterial blood pressure and systemic vascular resistance without a substantial reduction in resting heart rate, cardiac output, or stroke volume, apparently because of its combined α- and β-adrenergic blocking activity.

References

^ Fahed S, Grum DF, Papadimos TJ (2008). "Labetalol infusion for refractory hypertension causing severe hypotension and bradycardia: an issue of patient safety". Patient Saf Surg 2: 13. doi:10.1186/1754-9493-2-13. PMC 2429901. PMID 18505576.
^ http://www.bnf.org/bnf/bnf/56/2488.htm?q=%22labetalol%22
^ ^a ^b Katzung, Bertram G. (2006). Basic and clinical pharmacology. New York: McGraw-Hill Medical. p. 170. ISBN 0-07-145153-6.
^ Shiohara T, Kano Y (2007). "Lichen planus and lichenoid dermatoses". In Bolognia JL. Dermatology. St. Louis: Mosby. p. 161. ISBN 1-4160-2999-0.
^ Medicinal Chemistry of Adrenergics and Cholinergics
^ Riva E, Mennini T, Latini R (December 1991). "The alpha- and beta-adrenoceptor blocking activities of labetalol and its RR-SR (50:50) stereoisomers". Br. J. Pharmacol. 104 (4): 823–8. doi:10.1111/j.1476-5381.1991.tb12513.x. PMC 1908821. PMID 1687367.
^ D A Richards, J Tuckman, and B N Prichard (October 1976). "Assessment of alpha- and beta-adrenoceptor blocking actions of labetalol". Br J Clin Pharmacol 3 (5): 849–855. doi:10.1111/j.1365-2125.1976.tb00637.x. PMC 1428931. PMID 9968.

UpToDate Contents

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1. 頸動脈内膜剥離術および頸動脈ステント留置術の麻酔 anesthesia for carotid endarterectomy and carotid stenting
2. 腹部大動脈瘤ステントグラフト留置術に対する麻酔 anesthesia for endovascular aortic repair
3. 高血圧緊急症の治療に用いる薬物 drugs used for the treatment of hypertensive emergencies
4. 妊婦および出産後女性における高血圧のマネージメント management of hypertension in pregnant and postpartum women
5. β遮断剤の主な副作用 major side effects of beta blockers

English Journal

Role of antihypertensive therapy in mild to moderate pregnancy-induced hypertension: a prospective randomized study comparing labetalol with alpha methyldopa.

Molvi SN, Mir S, Rana VS, Jabeen F, Malik AR.SourceThe Department of Obstetrics and Gynecology, Government Lal Ded Hospital for Women, Government Medical College, Srinagar, Jammu and Kashmir, India, drsaba2007@yahoo.com.
Archives of gynecology and obstetrics.Arch Gynecol Obstet.2012 Jun;285(6):1553-62. Epub 2012 Jan 15.
BACKGROUND: Pregnancy-induced hypertension (PIH) is associated with adverse fetal and maternal outcome. The role of medication to control blood pressure (BP) in mild to moderate PIH is controversial.AIMS: We conducted a prospective study to investigate whether pharmacological treatment of mild to mo
PMID 22249781

Nifedipine versus labetalol in the treatment of hypertensive disorders of pregnancy.

Giannubilo SR, Bezzeccheri V, Cecchi S, Landi B, Battistoni GI, Vitali P, Cecchi L, Tranquilli AL.SourceDepartment of Clinical Sciences, Polytechnic University of Marche, "G. Salesi" Hospital via F. Corridoni 11, 60123, Ancona, Italy, s.giannubilo@univpm.it.
Archives of gynecology and obstetrics.Arch Gynecol Obstet.2012 May 12. [Epub ahead of print]
PURPOSE: To assess the maternal and fetal outcomes of pregnancies affected by hypertensive disorders treated with nifedipine versus labetalol.METHODS: A retrospective study in hypertensive patients treated during pregnancy with nifedipine or labetalol was conducted. After the charts review the patie
PMID 22581388

Hypertensive crisis in children.

Chandar J, Zilleruelo G.SourceDepartment of Pediatrics, Division of Pediatric Nephrology, Holtz Children's Hospital, University of Miami Miller School of Medicine, Miami, FL, USA.
Pediatric nephrology (Berlin, Germany).Pediatr Nephrol.2012 May;27(5):741-51. Epub 2011 Jul 20.
Hypertensive crisis is rare in children and is usually secondary to an underlying disease. There is strong evidence that the renin-angiotensin system plays an important role in the genesis of hypertensive crisis. An important principle in the management of children with hypertensive crisis is to det
PMID 21773822

Japanese Journal

Umbilical cord blood concentrations of labetalol hydrochloride administered to patients with pregnancy induced hypertension, and subsequent neonatal findings

Uematsu Kazuko,Kobayashi Eiko,Katsumoto Emi,Sugimoto Mitsuhiro,Kawakami Tadashi,Terajima Tomoko,Maezawa Kayoko,Kizu Junko
Hypertension Research in Pregnancy 1(2), 88-92, 2013
… Aim: We measured umbilical cord blood and maternal plasma concentrations of labetalol hydrochloride (labetalol) at delivery in women with pregnancy induced hypertension (PIH) who received labetalol treatment, and also investigated the influence of labetalol on neonatal findings.Methods: We surveyed background, neonatal findings, and health checkups after birth among PIH patients who received labetalol. …
NAID 130004638243

慢性高血圧症に降圧剤を使用し胎盤早期剥離-DIC後に腎障害が遷延した症例

岡本敦子,三好剛一,桂木真司 [他],根木玲子,山中薫,梅川孝,小林良成,堀内縁,神谷千津子,井出哲弥,田吹邦雄,吉原史樹,中村敏子,吉松淳
産婦人科の進歩 65(1), 69-74, 2013
妊娠中の高血圧に対し，本邦で従来使用されてきたヒドララジン，メチルドパの内服薬に加えて，ニフェジピン（妊娠20週以降に限る），ラベタロールの2剤について妊娠中の使用が認可された．今回，加重型妊娠高血圧腎症に対し選択的α2アゴニストとカルシウム拮抗薬を使用して妊娠継続を図ったが，常位胎盤早期剥離を発症し術後腎障害が遷延した症例を経験したので報告する．症例は34歳，0経妊0経産．27歳時より高血圧を指 …
NAID 130003362655

A CASE OF PHEOCHROMOCYTOMA ASSOCIATED WITH PREGNANCY

中村雅憲,小野田尚佳,渋谷雅常,山片重人,山枡誠一,西尾順子,田原英樹,石村栄治,石川哲郎,平川弘聖
日本臨床外科学会雑誌 66(4), 945-949, 2005
… Her blood pressure was able to be controlled with daily medication of labetalol 150mg and doxazosin 2mg, and the pregnancy was maintained without any problems for both the mother and fetus. …
NAID 130003604442

Role of α_1-Blockade in Congenital Long QT Syndrome : Investigation by Exercise Stress Test

Furushima Hiroshi,Chinushi Masaomi,Washizuka Takashi,Aizawa yoshifusa
Japanese circulation journal 65(7), 654-658, 2001-06-20
… In some patients refractory to β-blockade, the recurrence of arrhythmias is successfully prevented by left stellate ganglionectomy, and also by labetalol, a nonselective β-blockade with α_1-blocking action. …
NAID 110002568057

Related Pictures

★リンクテーブル★

リンク元	「HELLP症候群」「ラベタロール」
拡張検索	「labetalol hydrochloride」

「HELLP症候群」

Labetalol
Systematic (IUPAC) name
	(RS)-2-hydroxy-5-{1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl}benzamide
Clinical data
Trade names	Trandate
AHFS/Drugs.com	monograph
MedlinePlus	a685034
Pregnancy cat.	C; One of few drugs used for PIH;
Legal status	℞ Prescription only;
Routes	oral iv
Pharmacokinetic data
Bioavailability	25%
Protein binding	50%
Metabolism	hepatic pass metabolism,
Half-life	Tablet: 6-8 hours; IV: 5.5 hours
Excretion	Excreted in urine, not removed by hemodialysis
Identifiers
CAS number	36894-69-6
ATC code	C07AG01
PubChem	CID 3869
DrugBank	DB00598
ChemSpider	3734
UNII	R5H8897N95
KEGG	D08106
ChEBI	CHEBI:6343
ChEMBL	CHEMBL429
Chemical data
Formula	C19H24N2O3
Mol. mass	328.406 g/mol
	SMILES O=C(c1cc(ccc1O)C(O)CNC(C)CCc2ccccc2)N;
	InChI InChI=1S/C19H24N2O3/c1-13(7-8-14-5-3-2-4-6-14)21-12-18(23)15-9-10-17(22)16(11-15)19(20)24/h2-6,9-11,13,18,21-23H,7-8,12H2,1H3,(H2,20,24) ; Key:SGUAFYQXFOLMHL-UHFFFAOYSA-N ;
(what is this?) (verify)

　　[★]

英: HELLP syndrome hemolysis, elevated liver enzymes, low platelets
同: ヘルプ症候群

概念

溶血、肝臓酵素上昇、血小板減少を伴う。(NGY.399)

本疾患の溶血は微小血管障害性に起因する(参考6)ものであり、これで肝臓酵素上昇、血小板減少が説明できると思われる。

放置するとDICを発症する。(NGY.399)
妊娠高血圧症候群に伴うことが多い(NGY.399)。しかし15-20%の本疾患の患者では発症前に高血圧や蛋白尿を示していないため、妊娠高血圧腎症とは別の疾患概念と考える専門家もいる。(参考6)

疫学

発生頻度：0.021%、妊娠高血圧症候群の約2%(NGY.399)

臨床所見

右上腹部圧痛 80%
浮腫を伴う体重増加 60%
高血圧(重症 50%, 軽症 30%, なし 20%)

症状(NGY.399)

右季肋部または心窩部痛、悪心・嘔吐で発見される。

上腹部痛・心窩部痛(90%)、疲労感・倦怠感(90%)、嘔気・嘔吐(50%)

合併症

DIC 20%
常位胎盤早期剥離 16%
腎不全 7%
肝破裂
(子癇発作を起こしやすい)

診断

参考5

1)Sibai の基準

1. 肝機能：血清AST(GOT)値70U/l 以上、血清LDH 値600U/l 以上
2. 溶　血：血清間接ビリルビン値1.2mg/dl 以上、血清LDH 値600U/l 以上。病的赤血球の出現
3. 血小板数減少：血小板数10 万/μ l 以下

2)Sibai の基準を全て満たさなくても以下のような基準をひとつでも満たす場合には、HELLP 症候群発症を警戒し、注意を喚起する(妊娠中毒症学会HELLP 症候群検討小委員会)

1. 肝機能：血清AST(GOT)値、血清LDH 値が各施設の正常域を越えて高値の場合
2. 溶　血：血清間接ビリルビン値、血清LDH 値が各施設の正常域を越えて高値の場合
3. 血小板数減少：血小板数15 万/μ l 以下の場合
4. その他：血中アンチトロンビン活性が正常値の80% 未満の低下を示した場合やハプトグロビン値の低下した場合

鑑別疾患

治療

参考6

初期治療の方針：母体の安定化と胎児の評価を行い、急速遂娩の必要性を評価
1. termination：最良の治療法

以下に当てはまれば急速遂娩の適応：(1)妊娠34週以降である、(2)胎児の状態がnon-assureing statusである、(3)重篤な母体状態(多臓器不全、DIC、肝梗塞、肝出血、腎不全、早期胎盤剥離)である。

2. 降圧療法：βブロッカー(labetalol)、ヒドララジン、ニフェジピン。重篤な場合にはnitroprusside。
3. 子癇の予防：硫酸マグネシウムの投与
4. DIC出現時の治療：適宜新鮮凍結血漿、血小板、濃厚赤血球の輸血を行う。ATIII製剤、メシル酸ナファモスタット、ウリナスタチンを投与。
5. ステロイド療法：(エビデンスなし)産褥期の臨床症状、検査値改善に有効
6. 高度の溶血：ハプトグロビン

治療の禁忌

参考5

病態に交感神経活性化があるために、β受容体拮抗薬(リトドリン)、副交感神経遮断薬(ブスコパン)は血管攣縮を助長するため禁　　←　　前者はα受容体の相対的活性化、後者は交感神経優位となるため、と思う。

予後

周産期死亡率：30-40%

資料

1. HELLP, TTP, HUS の診断およびその管理

http://www.jsog.or.jp/PDF/51/5102-31.pdf

2. 妊娠高血圧症候群 - 日本産科婦人科学会 - 日産婦誌５８巻５号

http://www.jsog.or.jp/PDF/58/5805-061.pdf

3. 2）妊娠中毒症（妊娠高血圧症候群） HELLP 症候群 - 日本産科婦人科学会

http://www.jsog.or.jp/PDF/57/5709-257.pdf

4. HELLP症候群の診断と対応（児娩出後の悪化への対応） - 日本産科婦人科学会 - 日産婦誌62巻9号

http://www.jsog.or.jp/PDF/62/6209-273.pdf

5. C．産科疾患の診断・治療・管理 6．異常分娩の管理と処置 - 日産婦誌５６巻６号

http://www.jsog.or.jp/PDF/56/5606-107.pdf

6. [charged] HELLP syndrome - uptodate [1]

「ラベタロール」

　　[★]

英: labetalol
同: 塩酸ラベタロール labetalol hydrochloride
商: トランデート、アスクール、アドブロール、アミタロール、レスポリート、Normodyne
関: アドレナリン受容体、交感神経拮抗薬一覧

α1受容体遮断薬、β受容体遮断薬

「labetalol hydrochloride」

　　[★]

塩酸ラベタロール

関: dilevalol、labetalol

[pmid18505576-1] Fahed S, Grum DF, Papadimos TJ (2008). "Labetalol infusion for refractory hypertension causing severe hypotension and bradycardia: an issue of patient safety". Patient Saf Surg 2: 13. doi:10.1186/1754-9493-2-13. PMC 2429901. PMID 18505576.

[2] ttp://www.bnf.org/bnf/bnf/56/2488.htm?q=%22labetalol%22

[katzung10-3] Katzung, Bertram G. (2006). Basic and clinical pharmacology. New York: McGraw-Hill Medical. p. 170. ISBN 0-07-145153-6.

[bolognia-4] Shiohara T, Kano Y (2007). "Lichen planus and lichenoid dermatoses". In Bolognia JL. Dermatology. St. Louis: Mosby. p. 161. ISBN 1-4160-2999-0.

[5] Medicinal Chemistry of Adrenergics and Cholinergics

[pmid1687367-6] Riva E, Mennini T, Latini R (December 1991). "The alpha- and beta-adrenoceptor blocking activities of labetalol and its RR-SR (50:50) stereoisomers". Br. J. Pharmacol. 104 (4): 823–8. doi:10.1111/j.1476-5381.1991.tb12513.x. PMC 1908821. PMID 1687367.

[7] D A Richards, J Tuckman, and B N Prichard (October 1976). "Assessment of alpha- and beta-adrenoceptor blocking actions of labetalol". Br J Clin Pharmacol 3 (5): 849–855. doi:10.1111/j.1365-2125.1976.tb00637.x. PMC 1428931. PMID 9968.

匿名

検索

案内

案内

labetalol